P645: IBRUTINIB FOR TREATMENT OF RELAPSED-REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA: A MATCHING-ADJUSTED INDIRECT COMPARISON OF 3 RANDOMIZED PHASE 3 TRIALS
Authors: Paolo Ghia, Talha Munir, Jan Burger, John Seymour, Kerry Rogers, Hsin-Hui Huang, Carol Moreno, Lynne Neumayr, Chris Abbazio, Jeff Sharman
Journal: HemaSphere (2023)

Background: Ibrutinib is a standard therapy for patients with chronic lymphocytic leukemia (CLL), with demonstrated efficacy in the first-line and relapsed-refractory (R/R) settings. Within R/R CLL, single-agent ibrutinib was evaluated in 3 randomized phase 3 trials: RESONATE (vs ofatumumab), ALPINE (vs zanubrutinib), and ELEVATE-RR (vs acalabrutinib in patients with del(11q) or del(17p) mutations). Aims: The goal of this analysis was to evaluate the outcomes of Bruton’s tyrosine kinase inhibitor (BTKi) treatment in patients with R/R CLL by comparing the efficacy of ibrutinib in RESONATE to ALPINE and ELEVATE-RR, using a matching-adjusted indirect comparison (MAIC) analysis. Methods: Individual patient data (IPD) of ibrutinib-treated patients from RESONATE (NCT01578707) were separately match-adjusted to the ibrutinib-treated arms of 1) ALPINE (NCT03734016) and 2) ELEVATE-RR (NCT02477696) for key baseline characteristics: proportions of patients who were aged ≥75 years, had bulky disease, ≥3 or ≥4 prior treatments, b2 microglobulin >3.5 mg/L, and del(11q) or del(17p) mutations. For the comparison with ELEVATE-RR, only patients with del(17p) or del(11q) from RESONATE were included. Once ibrutinib-treated populations were matched, adjusted ORR and PFS from RESONATE were compared with the corresponding published outcomes from ALPINE and ELEVATE-RR; for PFS, IPD for ALPINE and ELEVATE-RR were extracted from published Kaplan-Meier curves. PFS hazard ratios (HRs) were calculated using a weighted Cox model. ORR calculation included CR + CRi + nPR + PR and was applied across the 3 studies. Results: The analysis comprised 785 ibrutinib-treated patients across RESONATE (n=195), ALPINE (n=325), and ELEVATE-RR (n=265). Following the omission of patients with missing values and the adjustment procedure, the effective RESONATE sample size was reduced to 95 patients (vs ALPINE) and to 69 patients (vs ELEVATE-RR). Median follow-up times were 36.0 months vs 29.6 months (RESONATE adjusted vs ALPINE published) and 36.1 vs 40.9 months (RESONATE adjusted vs ELEVATE-RR published). Two-year PFS (95% CI) among ibrutinib-treated patients in RESONATE adjusted sample and ALPINE were 81% (74%–90%) and 66% (60%–71%), respectively. The corresponding median PFS values were 40.7 months and 34.2 months, with the resulting HR (95%CI) of 0.57 (0.39–0.84) favoring RESONATE, P=0.0048 (Figure). The ORR (95% CI) estimates were 90% (86%–94%) and 74% (69%–79%), respectively (P<0.0001). Compared with the ELEVATE-RR ibrutinib arm, which included a greater proportion of patients with high-risk genetic features than ALPINE, the RESONATE adjusted sample had a greater 2-year PFS (79% [69%–89%] vs 69% [64%–75%]); this difference was not statistically significant. Median PFS values for RESONATE vs ELEVATE-RR were 41.2 vs 44.1 months (HR [95%CI] 0.85 [0.55–1.31], P=0.46), respectively, and the ORR estimates were 89% (83%–95%) and 80% (75%–85%) (P=0.0381). Summary/Conclusion: In phase 3 randomized trials in R/R CLL, continuous ibrutinib treatment was associated with robust PFS and ORR benefits. Ibrutinib outcomes were consistent between RESONATE and ELEVATE-RR; however, significant differences in the performance of ibrutinib within ALPINE were identified. Indirect comparisons have limitations, since each trial, protocol, and patient profile are unique; however, these results highlight the need for further research on which elements of protocol design, center selection, or treatment delivery may lead to a significant impact on the performance of a given BTKi in clinical trials.Keywords: ibrutinib, B cell chronic lymphocytic leukemia, Bruton’s tyrosine kinase inhibitor (BTKi), Chronic lymphocytic leukemia